Multiple sclerosis (MS) is a chronic inflammatory demyelinating neurodegenerative disease. There is evidence in both humans and rodents that stem cells in the adult central nervous system (CNS) can remyelinate. Remyelination fails in MS progression and age. The long-term objective of this application is to elucidate the role of microglia in inflammatory demyelination and remyelination. Microglia are the resident immune cells of the CNS. These cells respond to acute tissue damage, clear debris and regulate inflammation. Microglia participate in all aspects of MS but their exact role is unclear. To address microglial function in inflammatory demyelination and remyelination, we will utilize a novel transgenic mouse line (Cx3Cr1CreERT2/+:Rosa26DTA/+) that allows for inducible ablation of CNS microglia and an in-vivo model of MS. The two specific aims proposed further seek to characterize the role of microglia in a model a mouse model of multiple sclerosis. In particular, aim one will determine if microglia are necessary for demyelination and how does the fractalkine receptor Cx3Cr1 contribute to microglia function. Aim two will investigate how microglia influence adult stem cells' ability to proliferate and remyelination. Aim 2b, will determine if failures to remyelinate in the aged CNS are due to microglia dysfunction. MS is the most common cause of inflammatory neurological disability in young adults, affecting 1 in 400. It is incurable and irreversible. These studies should provide important new sights into microglia function in MS and determine the potential of microglia as a novel therapeutic target.